Proteins involved in cellular protection often also regulate cellular growth. In the heart, transcription factors, intracellular signaling kinases and phosphatases, membrane receptors/transporters and other stress- activated enzymes have all been shown to be involved in both cardiac protection against ischemia and the prototypical growth response of the organ, hypertrophy. However, the relevance of this observation beyond the context of individual proteins is unclear. We hypothesize that growth and protection of the heart are behaviors that arise from differential modulation of a shared core subproteome. In this R21, we will develop and employ new approaches to test this hypothesis. We recently made the tantalizing observation that loss of a member of the Tec family of non-receptor tyrosine kinases renders the heart resistant to both cardiac protection and hypertrophy. These findings-while completely unexpected- support the aforementioned hypothesis regarding growth and protection and provide an ideal tool to examine the relationship between these cardiac phenotypes. Despite evidence from previous studies in non-cardiac systems, the role of the Tec family in the heart is completely unknown. We will investigate these novel observations using a combination of animal models, quantitative proteomics and bioinformatics/mathematical modeling. Our approach will reveal emergent behaviors that engender phenotype which would be undetectable to solely hypothesis-driven research and is well-suited for the R21 mechanism because it is well-grounded in novel physiological and biochemical data, it is driven by innovative techniques, and it seeks to provide a conceptual advancement for cardiac signaling. Our aims are (1) to investigate the changes in mitochondrial and nuclear subproteomes during protection and hypertrophy and (2) to determine changes in intact protein complex formation by Tec family kinases during these same phenotypes. The goal of this application is to create a novel conceptual and experimental framework to interrogate the connection between cardiac growth and protection at a systems level. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Heart disease affects millions of people worldwide and is a critical focus for basic science research. We have discovered a new model of signaling protein involved in both the protection against heart attack-induced cell death and the induction of hypertrophic growth. We are taking an innovative approach to examine intracellular processes involved in these two states of the heart and developing new tools to examine signal transduction in the cardiovascular system.